Our work and that of others demonstrates that men and women with lower extremity peripheral arterial disease (PAD) have greater functional impairment and more rapid functional decline compared to those without PAD. The functional impairments documented in patients with PAD are associated with mobility loss, increased mortality, and poor quality of life. Preliminary evidence suggests that interventions to increase circulating levels of CD34+ cells may improve functional performance in PAD. However, three small clinical trials testing whether granulocyte monocyte colony stimulating factor (GM-CSF) improves walking performance in PAD yielded mixed results. The association of GM-CSF with improved walking performance in PAD is not definitively established. Preliminary data also suggest that lower extremity ischemia, induced during walking exercise, may increase circulating CD34+ cell levels, enhance homing of CD34+ cells to ischemic sites, and augment the ability of GM-CSF to improve walking performance in PAD. We propose a randomized controlled clinical trial (2 x 2 factorial design) of 240 participants with PAD who will be randomized to one of four arms: a) GM-CSF + supervised exercise therapy;b) GM-CSF therapy + an attention control group;c) placebo + supervised exercise therapy;and d) placebo + attention control group. In our primary specific aim, we will determine whether GM-CSF combined with supervised treadmill exercise significantly improves six-minute walk performance at 12-week follow-up, compared to GM-CSF alone and supervised exercise alone, respectively. We will also determine whether GM-CSF alone significantly improves six-minute walk performance at 12-week follow-up, compared to placebo. We will confirm that supervised treadmill exercise therapy significantly increases six-minute walk performance at 12-week follow- up, compared to an attention control group. In our secondary specific aim, we will determine whether GM-CSF combined with supervised treadmill exercise is associated with greater increases in brachial artery flow- mediated dilation (FMD) and maximal treadmill walking time at 12-week follow-up, compared to GM-CSF alone and supervised exercise alone, respectively. In our exploratory aim, we will establish the temporal trajectory of changes in six-minute walk performance, maximal treadmill walking time, and brachial artery FMD in response to GM-CSF. We will also establish the temporal trajectory of increases in progenitor cells in response to supervised treadmill exercise. In addition to establishing the therapeutic benefit of our interventions, this study is expected to identify biological pathways associated with improved functional performance in participants with PAD. PUBLIC HEALTH RELEVANCE: Lower extremity peripheral arterial disease (PAD) is common among older men and women and is associated with significant functional impairment and increased rates of functional decline compared to people without PAD. This proposed randomized controlled clinical trial will test whether the combination of granulocyte monocyte colony stimulating factor (GM-CSF) with supervised treadmill exercise improves functional performance more than either therapy alone. This study will also identify mechanisms by which functional performance is improved in people with PAD.